Assisted reproduction technology (ART) procedures typically require treatment with exogenous gonadotropins to stimulate growth and maturation of the ovarian follicles. When gonadotropins are used to treat anovulatory females, the goal is to replicate the normal menstrual cycle, when a single, dominant follicle matures prior to induction of ovulation. In contrast, for women undergoing in vitro fertilization (IVF), controlled ovarian stimulation (COS) is employed to stimulate the growth and maturation of several ovarian follicles, yielding multiple oocytes, which then are retrieved for use in the IVF procedure.
In connection with ART, COS, that secures development of multiple follicles it is essential to achieve the best possible chance for the patient to become pregnant. To obtain multiple follicle growth circulating levels of FSH need to surpass the physiological threshold level that triggers growth of responsive follicles for a longer period than the natural three to four day period. This is achieved by administration of exogenous FSH or by manipulating the pituitary gland to secrete enhanced amounts of FSH, and COS performed in the right way may easily result in the harvest of excess mature oocytes for in vitro fertilization (IVF).
In addition to stimulating follicular growth, an important function of FSH is to stimulate the development of LH-receptors on granulosa cells. LH-receptors are constitutively expressed on theca cells immediately surrounding the follicle and secure the production of—among other substances—androgens (i.e. androstenedione and testosterone) for conversion into oestrogens in the granulosa cell layer, but LH-receptors also have important functions in the granulosa cell layer of the follicle. Currently it is not known precisely when in follicular development LH-receptors become expressed on granulosa cells.
In the normal menstrual cycle, the LH-receptor is only activated by LH activity released from the pituitary, but hCG, which essentially is a pregnancy associated protein, may also bind and stimulate the LH-receptor. hCG has a longer half-life than LH and the accumulated in vivo activity of hCG (from equal doses of LH and hCG in an ampule) is usually considered to be 6 to 8 times higher than LH (Stockman P G W et al. Fertil Steril 1993; 60:175, Giudice E et al. J Clin Res 2001; 4:27).
Some preparations for COS only contain FSH while others contain a combination of FSH and LH-like activity (i.e. either LH or hCG alone or a mixture of LH and hCG). For instance, Menopur contains urine derived FSH and LH-like activity. In these preparations about 95 percent of the in vivo receptor mediated LH-like bioactivity derives from hCG due to its longer half-life (Van den Hooven H et al. RBM Online 2003; 7: 547). Recombinant LH is also available in a pure form as add on for COS (i.e. Luveris, Merck-Serono, Darmstadt, Germany). However, hCG for COS is only available in the presence of a product containing FSH and is not marketed in small doses to be used in connection with COS.
The clinical benefit of using LH-activity in connection with COS has been heavily debated during the past decade. Although a number of meta-analyses have suggested that the addition of LH-like activity, which in essence is provided via hCG, show an augmented baby-take-home rate as compared to pure FSH alone, this issue has not been clarified (Al-Inany H G et al., Reprod Biomed Online. 2008; 16: 81-88, Westergaard LW, Cochrane Database Syst Rev 2003; 1:CD003973., Al-Inany H G et al., Gynecol Endocrinol. 2009; 25:372-8). Adding to the complexity are differences between the FSH isoform profile of the most frequently used FSH containing hCG (i.e. Menopur (highly purified hMG containing urine derived FSH, LH and hCG)) and the pure FSH (i.e. recombinant FSH, Puregon or Gonal F). However, there is no doubt that LH levels can be reduced below a threshold limit at which adding LH-like activity will be helpful and there is also an upper threshold limit above which negative effects on treatment outcome become apparent. Thus LH-like activity should ideally remain in a therapeutically narrow window.
LH and CG are very homologous. In comparison to LH, CG has a C-terminal glycosylated extension that has been shown to be important for the longer half-life of CG. Human LH and hCG are more than 80% identical in sequence. Although both LH and hCG binds to and activate the LH-receptor, both hormones exist as a family of iso hormones that differ in their oligosaccharide composition. Each of the different isoforms affects the receptor in a specific way and may elicit variable cellular responses (Burgon P G et al., Endocrinology, 1996; 137:4827; Stanton P G et al., Mol Cell Endocrinol. 1996; 125:133-141.), as have also been shown for the different FSH isoforms (Barrios-de-Tomasi J, et al. Mol Cell Endocrinol. 2002; 186:189-98, Yding Andersen C & Ezcurra D, Reproductive Biology Insights 2011:4, 1-10). Thus the more subtle and fine-tuned effects of LH and hCG may actually differ. Recent studies presented at the ESHRE conference in Stockholm (July 2011) showed that LH acted much faster than hCG, but less efficient overall at the receptor level (L. Casarini et al., ESHRE Stockholm 2011-P312, Universita degli Studi di Modena, Italy). hCG is a pregnancy associated protein which is secreted following the implantation of the embryo starting around 8 days after ovulation. hCG is capable of stimulating the corpus luteum to remain active and continue its secretion of progesterone and other substances necessary for the pregnancy to become established. Despite the fact that levels of LH at that moment of the menstrual cycle are present in appreciable amounts, this level is insufficient to stimulate the corpus luteum further and unless the woman becomes pregnant the corpus luteum will regress, a menstrual bleeding will occur and a new menstrual cycle start. Although this difference between LH and hCG has puzzled science for some time, it has now been demonstrated that the LH-receptor (LH-R) changes during the luteal phase. The functional full-length receptor maintains its expression when hCG is present, whereas LH is unable to accomplish that (Dickinson R E et al., Endocrinology 150: 2873-2881, 2009). This demonstrates differences in the effect of LH and hCG during the luteal phase and this could suggest that LH and hCG also in the follicular phase of the menstrual cycle exert different effects at the receptor level.
It is now well recognised that LH-R expression on human granulosa cells is sufficient to drive follicular development from a diameter of around 10-12 millimeter and until ovulation with the presence of FSH in only small permissive amounts in connection with COS (Blockheel et al., 2009; Filicori et al., 1999). Thereby this stimulation resembles conditions of the natural menstrual cycle, in which levels of FSH is attenuated during the second half of the follicular phase, while levels of LH remain fairly constant and it has been shown that LH has a very strong stimulating effect on oestradiol production in granulosa cells from preovulatory follicles prior to the mid-cycle surge of gonadotropins. The ability to provide a more natural environment for the final maturation of the follicles is likely to provide oocytes that has an even better capacity to sustain fertilization, embryogenesis and implantation and subsequently result in a better reproductive outcome.
One of the most severe side-effects of COS is the occurrence of ovarian hyper stimulation syndrome (OHSS), which is a potential life threatening condition. Recent studies have shown that it is now possible to almost completely eliminate OHSS by the use of an agonist trigger for final follicular maturation (Humaidan P, Kol S, Papanikolaou E; Copenhagen GnRH Agonist Triggering Workshop Group. GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Hum Reprod Update. 2011; 17:510-24. PMID:21450755) without compromising the reproductive outcome. In combination with a GnRH antagonist down regulated pituitary function, a bolus of a GnRH agonist is capable of displacing the antagonist and cause a flare-up of gonadotropin release, which is then used as a signal for ovulation induction. However, subsequent to the flare up the agonist causes pituitary down regulation, which removes the stimulatory signals to the ovary. Removal of these stimuli also reduces the risk of OHSS. However, this down regulation also has a profound negative impact on the function of the corpus luteum and the reproductive outcome is unacceptably low. So in order to maintain a certain function of the corpus luteum it has successfully been attempted to add a bolus of hCG (1500 IU) at the time of oocyte retrieval and later on in the luteal phase. Alternatively daily injections of LH can rescue the luteal phase and provide a good reproductive outcome (A novel method of luteal supplementation with recombinant luteinizing hormone when a gonadotropin-releasing hormone agonist is used instead of human chorionic gonadotropin for ovulation triggering: a randomized prospective proof of concept study. Papanikolaou E G, Verpoest W, Fatemi H, Tarlatzis B, Devroey P, Tournaye H. Fertil Steril. 2011 Mar. 1; 95(3):1174-7. Epub 2010 Oct. 27. PMID: 20979997).
Despite recent advances in ART, ovarian stimulation through exogenous gonadotropins is not uniformly successful due, in part, to varying individual responses to treatment with gonadotropins. This variability complicates patient management and can result in multiple births and potentially life-threatening complications.
The gonadotropins form a family of structurally related glycoprotein hormones. Typical members include chorionic gonadotropin (CG), follicle stimulating hormone (FSH; follitropin), luteinizing hormone (LH; lutropin) and thyroid stimulating hormone (TSH; thyrotropin). FSH, LH and TSH are present in most vertebrate species and are synthesized and secreted by the pituitary. CG has so far been found only in primates, including humans, and in horses and is synthesized by placental tissue. FSH and LH are the pituitary hormones essential for follicular maturation and luteinization in the female and for testis maturation and spermatogenesis in the male. Gonadotropins are secreted by the pituitary gland under the control of hypothalamic gonadotropin-releasing hormone (GnRH). Follicle stimulating hormone (FSH) and luteinizing hormone (LH) are the pituitary hormones essential for follicular maturation (follicular development) and luteinization. FSH is required for follicular recruitment (i.e., the early growth of ovarian follicles) at the beginning of the spontaneous menstrual cycle, and it also supports mid- and late-stage follicular development.
In recent years very pure preparations, of the gonadotropins have become available through the use of recombinant DNA technology (see for instance Boime et al., Seminars in Reproductive Endocrinology 10, 45-50, 1992: “Expression of recombinant human FSH, LH and CG in mammalian cells”). The recombinant gonadotropins are of constant quality i.e. have reproducible biochemical and biological properties. Genomic and cDNA clones have been prepared for all subunits and their primary structure has been resolved. Moreover, Chinese Hamster Ovary (CHO) cells have been transfected with human gonadotropin subunit genes and these cells are shown to be capable of secreting intact dimers (e.g. Keene et al (1989), J. Biol. Chem., 264, 4769-4775; Van Wezenbeek et al (1990), in From clone to Clinic (eds Crommelin D. J. A. and Schellekens H.), 245-251). It has been demonstrated that the biochemical and biological characteristics of e.g. recombinant FSH are almost identical to those of natural FSH (Mannaerts et al (1991), Endocrinology, 129, 2623-2630). Moreover, pregnancies were achieved after controlled ovarian superovulation using recombinant FSH (Germond et al (1992), Lancet, 339, 1170; Devroey et al (1992), Lancet, 339, 1170-1171).
The gonadotropin may also be isolated from natural sources, e.g. from human urine, or the gonadotropin may be prepared in a (bio)synthetic way, c.f. by recombinant DNA techniques.
Gonadotrophins are widely used in clinical practice to treat women with WHO group II and WHO group I anovulation (World Health Organisation Technical Report 514, (1973)). Conventionally, follicular development is induced by administering hMG (human menopausal gonadotrophin) or u-hFSH (urinary human follicle stimulating hormone) at a dose of 75-150 IU/day. This dose is increased after a few days (usually five) by steps of 75 IU. It is rare to exceed 450 IU/day. When there is at least one follicle having a mean diameter of at least 18 mm and no more than two follicles having a mean diameter of at least 16 mm, a high dose (of 5000 IU for example) of hCG (human chorionic gonadotrophin) is administered to induce ovulation. This “conventional protocol” has been used successfully for more than 20 years. It carries some risks however, mainly in patients with polycystic ovaries or polysystic ovarian syndrome (PCOS).
These risks include the occurrence of OHSS, and a relatively high incidence of multiple pregnancies (Schenker et al, Fertil. Steril. 35: 105-123 (1981)). Although the majority of multiple pregnancies are twins, induction of ovulation contributes to one third of the high rank multiple births in the UK (Levene et al, Br. J. Obstet. Gynacol. 99: 607-613 (1992)).
Careful monitoring during treatment by ultrasound (US) and assessment of serum oestradiol (E2) have reduced these risks but have not been able to prevent them in all patients. These problems are directly related to the difficulty of obtaining the growth of a single dominant follicle leading to non-physiological multifollicular development.
FSH is administered therapeutically to induce follicular development in anovulatory women and women undergoing COS. In traditional ovulatory stimulation methods, FSH is administered throughout treatment until shortly before the oocytes are retrieved. This continued stimulation by FSH usually causes multiple follicular development and can in combination with an exogenous bolus of hCG to induce ovulation lead to a potentially fatal condition, OHSS. It has now been estimated that COS is fatal to otherwise healthy patients in around 3 per 100,000 stimulation cycles. Decreasing the dosage of FSH can reduce the risk of OHSS, but low FSH dosages yield inadequate number of follicles and thus lower the chances of success in assisted reproduction.
LH functions during all stages of a normal menstrual cycle. LH stimulates the theca cells of the follicle to produce the androgen substrate which is converted into estrogen by the aromatase system in the granulosa cells. During the late stages of follicle maturation, approximately 5 to 7 days before ovulation, large ovarian follicles begin to express LH receptors in granulosa cells, which render those follicles responsive to LH for continued maturation and development. Hillier et al., Mol. Cell. Endocrinol. 100:51 (1994), Campbell et al. J. Reprod. Fertil. 117:244 (1999). Next, a mid-cycle surge of LH triggers the final stage of follicular maturation and ovulation in a normal menstrual cycle. Ovulation follows the mid-cycle LH surge within 24 to 48 hours. Finally, in the second part of the menstrual cycle, the luteal phase, LH stimulates production of estrogen and progesterone in the corpus luteum of the ovary as it prepares the uterus for implantation and pregnancy.
In ovarian stimulation protocols, hCG can serve as a source of LH activity because hCG and LH act through the same receptor. Filicori et al. Human Reprod. 17:2009 (2002a); Martin et al., Fertil. Steril. 76: 0-49 (2002). Relative to LH, hCG has a longer half-life and, hence, is more potent in vivo than LH, although the literature tends to treat hCG and LH as fungible. Indeed, the scientific literature generally does not mention determining the source of LH activity in naturally-derived gonadotropin preparations.
The literature discloses using LH activity or low doses of hCG in combination with FSH throughout ovulatory stimulation, but guidance regarding effective amounts and timing of LH activity supplementation is lacking. For example, the abstract of Martin et al, Fertil. Steril. 76: 0-49 (2002), discloses administering 2.5 μg recombinant hCG daily (maintaining serum hCG levels from 1-3 mIU/mL) during ovulatory stimulation. Gordon et al. disclose administering 75 IU FSH with 0, 1, 25, and 75 IU LH activity. Human Reprod. 12 (Suppl. 1): 52 (1997a); ibid.: 53 (1997b).
Published studies disclose administering LH activity, throughout stimulation, at FSH to LH ratios of 150:0, 150:37.5, 150:75, and 150:150. Filicori et al. (2002a). Further, the literature documents supplementing FSH stimulation with 50 IU hCG/day (Filicori et al., J. Clin. Endocrinol. & Metabol. 84: 2659 (1999)), and protocols in which 150 IU FSH is administered for 7 days, followed by treatment with FSH-to-hCG ratios of 150:0, 50:50, 25:100, and 0:200 (ibid. 87:1156 (2002c) and US20080108571).
During the last 10 years, a new protocol has been designed (the “chronic low dose protocol”) and tested in order to reduce further the incidence of the complications of gonadotrophin therapy (Seibel et al, Int. J. Fertil., 29: 338-339 (1984); Buvat et al, Fertil. Steril., 52: 553-559 (1989); Hamilton-Fairley et al, Human Reprod. 6: 1095-1099 (1991); Sagle et al, Fertil Steril., 55: 56-60 (1991); Shoham et al, Fertil. Steril., 55: 1051-1056 (1991); Meldrum, Fertil Steril., 55: 1039-1040 (1991)). This protocol starts with a low dose of FSH or hMG (75 IU/day) and no dose adjustment before seven or preferably 14 days of treatment. If a dose adjustment is required, this is made by incremental steps of only 37.5 IU. In addition, each subsequent increase may only be effected after seven days of treatment at a given dose. The concept of this chronic low dose protocol is to find the threshold amount of FSH necessary to promote unifolliculogenesis. Encouraging results have been published so far, showing that this approach reduces the mean number of preovulatory follicles, the average preovulatory E2 level and the size of the ovary at mid-luteal phase.
However, despite the use of the chronic low dose protocol, some treatment cycles still have to be cancelled due to an over-response (e.g. where there are more than 3 follicles with a mean diameter of 16 mm or more). In addition, the multiple pregnancy rate, although clearly improved when compared to the conventional protocol, is still higher than in spontaneous conception cycles i.e. 5-10% in induced ovulation as opposed to 1.5% in spontaneous cycles. This is due to the fact that development of a single pre-ovulatory follicle is obtained in only about two thirds to three quarters of the induced cycles and follicles having a mean diameter of 15 mm or less are usually not considered when assessing the number of pre-ovulatory follicles on the day of hCG administration (Buvat et al, FertiL Steril., 52: 553-559 (1989); Hamilton-Fairley et al, Human Reprod. 6: 1095-1099 (1991)). It is, however, not clear whether follicles with a mean diameter of 14 to 15 mm, or even less, on the day of hCG administration, will ovulate and lead to the release of a healthy fertilisable oocyte. Thus, it would be desirable to have improvements in FSH-induced follicular development treatment in which the rates of multiple pregnancy and cycle cancellation are reduced.
Antral follicle growth is induced by FSH. Continuously throughout life and up to the menopause, some follicles enter a growth phase which is interrupted by regression and atresia before reaching the full maturity stage of preovulatory status (Hillier, Hum. Reprod., 9: 181-191 (1994)). During the growth phase, most follicles could be rescued from atresia, provided that it is exposed to a sufficient concentration of FSH. The level of FSH required to prevent atresia and promote further growth of a follicle is called the “FSH threshold” level (Brown, Aus. NZJ Obstet. Gynecol., 18: 47-55 (1987). The FSH threshold level varies with time and, at a given time-point, the follicles which are currently in a growth phase have different FSH threshold levels. This is the rationale on which the “chronic low dose” protocol is based. A progressive and cautious increase in the dose of FSH is used for finding the threshold level of a minimal number of follicles, and hopefully achieving mono-ovulation.
It is known that LH also contributes to the phenomenon of follicle dominance and mono-ovulation. Indeed, although some LH is essential for E2 synthesis during follicular development, there is evidence that excessive exposure to LH will trigger follicular atresia and suppress granulosa cell proliferation. Developing follicles appear thus to have finite requirements for stimulation by LH, beyond which normal follicular development ceases. This is the “LH ceiling” concept (Hillier, Hum. Reprod., 9: 181-191 (1994)). It is believed that, at a given time-point, the follicles which are currently in a growth phase have different LH ceiling levels. It is suggested that the more mature follicles are more resistant to the atretic action of LH than less mature follicles.
Two cases of WHO group I anovulation treated by either FSH alone or hMG using a step-up protocol have been reported (Glasier et al, Journal of ndocrinology, 119 A-159 (1988)). The “FSH alone” cycle had a much larger number of mature follicles than the hMG cycle, possibly supporting a role of LH in the atresia of secondary follicles. Afterwards two comparative studies were published. In a first cross-over study in 10 hypogonadotrophic hypogonadal women, a striking difference was recorded in terms of preovulatory E2 levels, but follicular count was not reported (Couzinet et al, J. Clin. Endocrinol. Metab. 66: 552-556 (1988)). A second cross-over study in 9 hypogonadotrophic hypogonadal women reported a mean number of follicles having a mean diameter of more than 16 mm on the day of hCG administration of 2.0 (0.7 in hMG-treated cycles and of 1.2 in FSH-treated cycles (Shoham et al, FertiL Steril., 55: 1051-1056 (1991)). No information is available on the number of smaller follicles.
More recently, the results of administering 150 IU hFSH (human FSH) and 75 IU r-hLH (recombinant human LH) to a single patient with unmeasurably low serum FSH, LH and E2 concentrations have been published (Hall et al, The Lancet, 344 (8918): 334-335 (1994)). Administration of r-hLH and r-hFSH caused E2 levels to be raised, and the total number of follicles of 10 mm or more in diameter to be reduced, as compared to administration of hFSH alone. However, the number of large follicles remained sufficiently high to suggest an unacceptably high multiple pregnancy rate.
A further study compared the effect of administering r-hLH (at a dose of either 300 IU/day or 750 IU/day) and r-hFSH to normal ovulatory women after treatment with FSH for stimulating multiple follicular development prior to intrauterine implantation (Sullivan et al, Journal of Clinical Endocrinology and Metabolism, 84,228-232, 1999)). The results indicate that serum E2 levels were raised in those women who received LH, although no measurements of the number and size of follicles were made and a multiple pregnancy occurred in the group receiving 750 IU/day of LH.
The literature documents other compositions that contain both FSH and LH activity, as well as use of FSH in combination with LH activity. For example, PCT application WO 00/67778, published Nov. 16, 2000, is directed to using LH or an equivalent amount of hCG in combination with FSH to induce follicular development in anovulatory women. More particularly, the '778 application discloses administering LH or “a biologically-active analogue thereof” in doses of 100 to 1500 IU per day (page 4, lines 26-29) and in FSH:LH ratios that range from 1:1.5 to 1:20 (id., lines 16-18).
U.S. Pat. No. 5,929,028 is directed to liquid formulations that contain one or more natural or recombinant gonadotropins, including FSH, LH, and hCG. The '028 patent discusses naturally derived compositions of human menopausal gonadotropin (hMG), which have FSH and LH activities in a ratio of approximately 1:1, but mentions no ratio of FSH to LH activity other than the 1:1 ratio of commercial hMG preparations.
Additionally, there are commercial formulations that contain both FSH and LH. Human-derived preparations are available containing 75 IU FSH with 75 IU LH activity (Pergonal, Humegon, Menogon, Repronex, and Menopur) and 75 IU FSH with 25 or 35 IU LH activity (Normegon and Pergogreen).
It is conventional wisdom, however, that “excessive” LH levels, albeit ill-defined, result in follicular atresia, suppression of granulosa cell proliferation, and premature luteinization. See, generally, Filicori, Fertil. Steril. 79: 253 (2003). Although recent work suggests otherwise, a notion persists in the field that LH activity levels must be within a certain range, and that levels below or above an “LH ceiling” impair normal follicle development. Shoham, Fertil. Steril. 70: 1170 (2002).
In summary, there is published evidence that supplementing FSH with LH activity during ovulation induction reduces the duration of treatment and the amount of gonadotropin used to achieve proper follicle development. Filicori et al. (1999), (2002b). On the other hand, the belief persists that “high” LH activity levels negatively impacts follicle development.
Despite the numerous advances in COS protocols there is a need for further improvement and to remove the occurrence of OHSS, to improve the subsequent implantation rates and to improve the convenience for the females undergoing assisted reproductive therapy as well as safety.
That belief has guided the conventional ovarian-stimulation paradigm, which involves administration of FSH throughout controlled ovarian stimulation. Exogenous LH activity is deemed unnecessary and even detrimental during the early to middle stages of follicular development. Accordingly, the traditional means of ovarian stimulation entail treatment with FSH alone, typically at 75-300 IU/day. In this traditional protocol, LH activity is administered to induce ovulation only after the follicle reaches a certain stage of development. Only recently has LH activity been administered throughout treatment, and the optimal amount and timing of LH activity that is effective in this context remains controversial.
In order for boys to develop normal fertility, both testicles need to be located outside of the body at a lower temperature in the scrotum. If one or both testicles remain at body temperature for prolonged periods of time, fertility may be compromised and the ability to produce functional sperm cells in adult life may be hampered. In order to reduce the negative impact on fertility by an undescended testicle, it is usually physically moved to the scrotum through an operation or by hormone treatment with hCG that cause the testicle(s) to move to the scrotum. hCG stimulates production of testicular steroid hormones by stimulating the Leydig cells to produce androgens. The exact mechanism of action of the increased levels of androgens in causing the testicule(s) to move to the scrotum is not known precisely.
The frequency of at least one undecended testicles among boys is about 3% of full-term and 30% of premature infant boys. However, during the first year of life the majority of testicles within the body arrive in the scrotum themselves (the majority within three months), making the true incidence of cryptorchidism around 1% overall. The effect of hCG is well documented but due to differences in patient age, treatment schedules, and possible inclusion of retractile testes, very divergent results have been reported and the true efficacy is not known. A number of different dosage schedules have been reported, ranging from 3-15 doses given twice a week (10 injections over 5 weeks is common). One of the most common schedules prescribes 250 IU/dose in young infants, 500 IU/dose in children 6 years or younger, and 1000 IU/dose in individuals older than 6 years.
Men with hypogonadotropic hypogonadism have an inability to carry out pituitary release of the gonadotropins LH and FSH. Various genetic defects may cause a defect in the hypothalamus resulting in a deficiency in the release of gonadotropin releasing hormone (GnRH), which in turn causes the pituitary to reduce release in FSH and LH. One such condition is the so-called Kallmann syndrome that affects approximately 1:10.000 males and 1:50.000 females. Apart from affecting the fertility, the main health problem to both men and women is oesteoporosis.
When levels of LH are low the androgen production in men is reduced and they are often infertile and show reduced male characteristics. Treatment is focused on restoring the deficient hormones. Males are administered hCG or testosterone. A number of different testosterone preparations are available; the more widely used ones only requires administering with monthly intervals. However, to induce sperm production and fertility in these men, it is required to with administration of hCG, because exogenously administered testosterone reaching the testicles via circulation seldom reaches intratesticular levels sufficient to cause sperm production. It appears more effective using hCG to stimulate the testicular androgen production sufficiently to provoke sperm production often in combination with FSH administration. Since sperm production from the spermatogonial stage to the fully mature spermatozoa takes 60 to 70 days it is often a lengthy process with multiple injections of hCG for initiation of sperm production.